Targeting Language-specific and Executive-control Networks With Transcranial Direct Current Stimulation in Logopenic Variant PPA

Официальное название

Targeting Language-specific and Executive-control Networks With Transcranial Direct Current Stimulation in Aphasic AD (Logopenic Variant PPA)

Обзор

AD afflicts over 5.5. million Americans and is one of the most expensive diseases worldwide. In AD the variant in which language functions are most affected are referred to as 'logopenic variant Primary Progressive Aphasia' (lvPPA). Language deficits dramatically impair communication and quality of life for both patients and caregivers. PPA usually has an early onset (50-65 years of age), detrimentally affecting work and family life. Studies have identified verbal short-term memory/working memory (vSTM/WM) as a primary deficit and cause of language impairment. In the first cycle of this award, the investigators asked the question of whether language therapy effects could be augmented by electrical stimulation. The investigators conducted the largest to-date randomized, double-blind, sham-controlled, crossover, clinical trial to determine the effects of transcranial direct current stimulation (tDCS) in PPA. The investigators found that tDCS over the left inferior frontal gyrus (L\_IFG), one of the major language hubs in the brain, significantly enhanced the effects of a written naming and spelling intervention. In addition, findings demonstrated that tDCS modulates functional connectivity between the stimulated area and other networks (e.g. functionally and structurally connected areas), and that tDCS modulates the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). In terms of tDCS, the investigators have been identified several predictors to determine the beneficience of tDCS including (a) PPA variant, (b) initial performance on cognitive/language tasks, particularly vSTM/WM, and (c) initial white-matter integrity and structure. These findings support the notion that tDCS benefits generalize beyond the treatment tasks and has led to the important question of the present study: How can we implement treatments to product benefits that maximally generalize to untrained but vital language/cognitive functions. To address the above question, the investigators will test recent neuroplasticity theories that claim that the benefits of neuromodulation to language-specific areas generalize to other language functions within the language network, while neuromodulation of a domain-general/multiple-demands area generalizes to both domain-general, executive and language functions. The two areas to be stimulated will be the supramarginal gyrus (SMG) and left dorsolateral prefrontal cortex (DLPFC) respectively. The left supramarginal gyrus (L\_SMG) in particular, specializes in phonological processing, namely phonological verbal short-term memory (vSTM), i.e., the ability to temporarily store phonological (and graphemic) information in order. The domain of vSTM affects many language tasks (repetition, naming, syntax), which makes it an ideal treatment target and the L\_SMG an ideal stimulation target, since generalization of tDCS effects to other language tasks is driven by the function (computation) of the stimulated area. By testing a fundamental principle of neuromodulation in a devastating neurodegenerative disorder, the investigators will significantly advance the field of neurorehabilitation in early-onset dementias. Aim 1: To determine whether vSTM/WM behavioral therapy combined with high definition (HD)-tDCS over the L\_SMG will induce more generalization to language-specific tasks than to executive tasks, whereas stimulation over the LDPFC will induce equivalent generalization to both executive and language-specific tasks. Aim 2: To understand the mechanism of tDCS by measuring tDCS-induced changes in network functional connectivity (FC) and GABA in the LSMG and LDPFC. The investigators will carry out resting-state functional magnetic resonance imaging (rsfMRI), (MPRAGE), diffusion-weighted imaging (DWI), perfusion imaging (pCASL), and magnetic resonance spectroscopy (MRS), before, after, and 3-months post-intervention. Aim 3: To identify the neural, cognitive, physiological, clinical and demographic characteristics (biomarkers) that predict sham, tDCS, and tDCS vs. sham effects on vSTM and related language tasks in PPA. The investigators will evaluate neural (functional and structural connectivity, cortical volume, neuropeptides, and perfusion), cognitive (memory, attention, executive) and language functions, clinical (severity), physiological (sleep), and demographic (age, gender) characteristics, and the investigators will analyze the effects on vSTM and other language/cognitive outcomes immediately after intervention and at 3 months post-intervention.

Подробное описание

This proposal will extend the investigators' previous award, which provided the first evidence from a clinical trial (double-blind, sham-controlled, crossover), on the beneficial effects of transcranial direct current stimulation (tDCS) over the left inferior frontal gyrus (L\_IFG) in primary progressive aphasia (PPA), a debilitating neurodegenerative disorder affecting primarily language functions. The investigators' previous studies, although it established the augmentative effects of tDCS in PPA and shed light on its possible mechanisms, the investigators also revealed a fundamental gap in the investigators' knowledge, namely the effect different tDCS effects In this present study, the investigators will directly address this knowledge gap by stimulating two areas of atrophy in PPA, the parietal cortex, the epicenter of vSTM/WM within the language network, and the frontal cortex, a major executive and multi-domain area, to test the tDCS effects in PPA, uncover the mechanisms, and estimate tDCS predictors.

Вмешательства

• Устройство High-definition active tDCS (HD-tDCS) + "Repeat After Me" (RAM) Treatment
  Device: Active HD-tDCS \& "Repeat After Me" (RAM) Treatment Stimulation will be delivered by a battery-driven constant current stimulator. Electrical current will be administered to left supramarginal gyrus (L\_SMG). The stimulation will be delivered at an intensity of 2 milliamperes (mA) (estimated current density 0.04 mA/cm2; estimated total charge 0.048 Coulombs/cm2) in a ramp-like fashion for a maximum of 20 minutes. Participants will receive RAM consisting of word span repetition span (in
• Устройство Sham + "Repeat After Me" (RAM) Treatment
  Device: Sham Current will be administered in a ramp-like fashion but after the ramping phase the intensity will drop to 0 mA. Current under the Sham condition will last for a maximum of 30 seconds. Participants will receive RAM consisting of word span repetition span (increasing length, with/without response delay). Span tasks will be manipulated in terms of list length (single words, pair, triplets) and response delay (1 sec, 5 sec). Each list will consist of 10 spans. During each trial, parti

Первичные конечные точки

• Change in percent accuracy on word repetition (no delay) assessed by Temple Assessment of Language and Short-Term Memory in Aphasia (TALSA) Test 3 [Срок оценки: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention]
• Change in percent accuracy on word repetition (with 5-sec delay) assessed by TALSA Test 3 [Срок оценки: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention]
• Change in percent accuracy on word span assessed by TALSA Test 14 [Срок оценки: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention]

Вторичные конечные точки (12)

• Change in TALSA sentence repetition (Test 7) score [Срок оценки: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention]
• Change in National Alzheimer's Coordinating Center's (NACC) sentence repetition score [Срок оценки: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention]
• Change in digit span forward score [Срок оценки: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention]
• Change in visual rhyming score [Срок оценки: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention]
• Change in Northwestern Anagram Test (NAT) score [Срок оценки: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention]
• Change in NAVS - Argument Structure Production Test (ASPT) score [Срок оценки: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention]
• Change in spelling of non-words to dictation score [Срок оценки: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention]
• Change in Apraxia Battery of Adults-Second Edition (ABA-2) score [Срок оценки: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention]
• Change in spelling of words to dictation score [Срок оценки: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention]
• Change in NAVS - Sentence Comprehension Test score [Срок оценки: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention]
• Change in Subject-Relative, Object-Relative, Active Passive (SOAP): Test of Syntactic Complexity score [Срок оценки: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention]
• Change in Boston Naming Test (Short-Version) score [Срок оценки: Before intervention, immediately after intervention, 1 month post intervention, 3 months post intervention]

Критерии участия

Критерии включения

• Must be between 50-80 years of age.
• Must be right-handed.
• Must be proficient in English.
• Must have a minimum of high-school education.
• Must be diagnosed with Primary Progressive Aphasia (PPA) or dementia.
• Participants will be diagnosed with PPA or with any of the PPA variants in specialized or early dementias clinics at Johns Hopkins University or other specialized centers in the US based on the current consensus criteria.
• Healthy age- and education-matched controls: The investigators will include 30 healthy age- and education-matched controls, usually spouses, to maximize similarity in terms of other demographic or life-style factors that contribute to language and cognitive performance.

Критерии исключения

• People with previous neurological disease including vascular dementia (e.g., stroke, developmental dyslexia, dysgraphia or attentional deficit).
• People with uncorrected hearing loss
• People with uncorrected visual acuity loss.
• People with advanced dementia or severe language impairments: Mini Mental State -Examination (MMSE)<18, or Montreal Cognitive Assessment (MOCA)<15, or language Frontotemporal Dementia specific - Clinical Dementia Rating (FTD-CDR)<=2.
• Left handed individuals.
• People with pre-existing psychiatric disorders such as behavioral disturbances, severe depression, or schizophrenia that do not allow these people to comply or follow the study schedule and requirements such as repeated evaluation and therapy.

Exclusion Criteria for MRI Participation:

• People with severe claustrophobia.
• People with cardiac pacemakers or ferromagnetic implants.
• Pregnant women.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Перекрёстный дизайн

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Johns Hopkins Hospital — Baltimore

Публикации

• Tsapkini K, Frangakis C, Gomez Y, Davis C, Hillis AE. Augmentation of spelling therapy with transcranial direct current stimulation in primary progressive aphasia: Preliminary results and challenges. Aphasiology. 2014;28(8-9):1112-1130. doi: 10.1080/02687038.2014.930410. PMID 26097278
• Tsapkini K, Webster KT, Ficek BN, Desmond JE, Onyike CU, Rapp B, Frangakis CE, Hillis AE. Electrical brain stimulation in different variants of primary progressive aphasia: A randomized clinical trial. Alzheimers Dement (N Y). 2018 Sep 5;4:461-472. doi: 10.1016/j.trci.2018.08.002. eCollection 2018. PMID 30258975
• Ficek BN, Wang Z, Zhao Y, Webster KT, Desmond JE, Hillis AE, Frangakis C, Vasconcellos Faria A, Caffo B, Tsapkini K. The effect of tDCS on functional connectivity in primary progressive aphasia. Neuroimage Clin. 2018 May 21;19:703-715. doi: 10.1016/j.nicl.2018.05.023. eCollection 2018. PMID 30009127
• Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, Ogar JM, Rohrer JD, Black S, Boeve BF, Manes F, Dronkers NF, Vandenberghe R, Rascovsky K, Patterson K, Miller BL, Knopman DS, Hodges JR, Mesulam MM, Grossman M. Classification of primary progressive aphasia and its variants. Neurology. 2011 Mar 15;76(11):1006-14. doi: 10.1212/WNL.0b013e31821103e6. Epub 2011 Feb 16. PMID 21325651
• Neophytou K, Wiley RW, Rapp B, Tsapkini K. The use of spelling for variant classification in primary progressive aphasia: Theoretical and practical implications. Neuropsychologia. 2019 Oct;133:107157. doi: 10.1016/j.neuropsychologia.2019.107157. Epub 2019 Aug 8. PMID 31401078
• Champod AS, Petrides M. Dissociable roles of the posterior parietal and the prefrontal cortex in manipulation and monitoring processes. Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14837-42. doi: 10.1073/pnas.0607101104. Epub 2007 Sep 5. PMID 17804811
• Champod AS, Petrides M. Dissociation within the frontoparietal network in verbal working memory: a parametric functional magnetic resonance imaging study. J Neurosci. 2010 Mar 10;30(10):3849-56. doi: 10.1523/JNEUROSCI.0097-10.2010. PMID 20220020
• Riello M, Faria AV, Ficek B, Webster K, Onyike CU, Desmond J, Frangakis C, Tsapkini K. The Role of Language Severity and Education in Explaining Performance on Object and Action Naming in Primary Progressive Aphasia. Front Aging Neurosci. 2018 Oct 30;10:346. doi: 10.3389/fnagi.2018.00346. eCollection 2018. PMID 30425638

Идентификаторы

NCT: NCT03887481 · IRB00201027 · R01AG075404

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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